Activity-Directed Synthesis: A Flexible Approach for Lead Generation

Activity-directed synthesis (ADS) is a structure-blind, functional-driven molecular discovery approach. In this Concept, four case studies highlight the general applicability of ADS and showcase its flexibility to support different medicinal chemistry strategies. ADS deliberately harnesses reactions with multiple possible outcomes, and allows many chemotypes to be evaluated in parallel. Resources are focused on bioactive molecules, which emerge in tandem with associated synthetic routes. Some of the future challenges for ADS are highlighted, including the realisation of an autonomous molecular discovery platform. The prospects for ADS to become a mainstream lead generation approach are discussed.     

Predicting Forest Age Classes from High Spatial Resolution Remotely Sensed Imagery Using Voronoi Polygon Aggregation

Efficient identification of forest age is useful for forest management and ecological applications. Here we propose a user-assisted method for determining forest age using high spatial resolution remotely sensed imagery. This method requires individual trees to be extracted from imagery and represented as points. We use a local maximum filter to generate points that are converted to Voronoi polygons. Properties of the Voronoi polygons are correlated with forest age and used to aggregate points (trees) into areas (stands) based on three forest age classes. Accuracy of the aggregation ranges from approximately 68% to 78% and identification of the mature class is more consistent and accurate than the younger classes.     

Diagnosis of systemic causes of uveitis; a matter of ophthalmologist and internist

OBJECTIVE: To assess how often the aetiology is established in patients with uveitis, what systemic disease are found and what is the contribution of the internist to the diagnostic process. DESIGN: Retrospective study. SETTING: University Hospital Leiden, the Netherlands. METHOD: From January 1987 to April 1992, 342 patients presented with uveitis. All patients underwent a standard ophthalmological examination. Referral to an internist and individualised laboratory screening followed in patients with recurrent, chronic, bilateral or panuveitis. Recorded were: ophthalmological data, results of laboratory screening, results of analysis by the internist, final diagnosis and presence of systemic disease. RESULTS: 149 (44%) patients were examined by the internist, 18 (5.2%) were seen by another specialist. In 169 (49%) patients a specific diagnosis was made. 74 (22%) had a systemic disease, 74 a primary ocular disease. In 28 (8%) a systemic disease was presumed (5% were HLA-B27 positive, 3% had abnormal laboratory results); 5 (1%) patients had endophthalmitis as a complication of a septic process. CONCLUSION: In approximately 1/3 of the patients with uveitis a systemic disease was found. Examination by the internist tailored to the individual patient is essential in the evaluation of uveitis patients.     

Comparison of two methods of surfactant administration and the effect on dosing-associated hypoxemia

OBJECTIVE: The purpose of our study was to test the hypothesis that surfactant dosing through a proximal sideport adapter on an endotracheal tube leads to more dosing-associated hypoxemia compared with a method of dosing that uses a double-lumen endotracheal tube. STUDY DESIGN: Using adequate sample size to compare significant changes in O2 saturation (power > 0.8, alpha < 0.05) we enrolled 36 infants with respiratory distress syndrome in this randomized trial. A 10% change in O2 saturation was considered clinically significant. Nineteen infants received 38 doses of surfactant through the sideport adapter. Seventeen infants received 31 doses of surfactant through the nonventilation lumen of a double-lumen endotracheal tube. Two main outcome measures were assessed: time-averaged O2 saturation values 30 minutes after dosing and the largest absolute fall in O2 saturation for each patient. RESULTS AND CONCLUSIONS: Time-averaged O2 saturation measures were higher in the proximal sideport group (p = 0.02), but the magnitude of difference was probably not clinically significant. No significant difference was detected between groups when we compared largest absolute drop in O2 saturation. Secondary analyses found no effect of birth weight or dose number (second vs third dose) on either outcome measure.     

Stochastic model for a wavelike exothermal reaction in condensed heterogeneous systems

The labile protons of two 32-base-pair, four-arm models of immobile Holliday junctions have been studied by two-dimensional 1H nuclear magnetic resonance (NMR) spectroscopy. Overlap of resonances in the imino-imino region of two-dimensional nuclear Overhauser enhancement (NOE) spectra necessitates the use of a multi-pathway approach for obtaining sequence-specific assignments wherein all possible NOE connectivities to the labile protons are utilized, including those from the 2H of adenine, 5CH3 of thymine, and 5H of cytosine. Resonance assignments are obtained for all slowly exchanging imino and cytosine amino protons. Base-pairing up to and including the junction point is found in all four arms of both Holliday junctions. Several cross-arm NOE connectivities are identified and can be used to infer the geometry of the helical stacking domains. The two Holliday junctions studied, which differ only by the exchange of two base pairs at the branch point, appear to have opposite arm stacking geometries. These assignments form an important part of the critical background for detailed NMR analysis of Holliday junction structure and dynamics.     

Oncological outcomes of operative treatment of subcutaneous soft-tissue sarcomas of the extremities

We reviewed the cases of sixty-two patients who had had a subcutaneous sarcoma to determine the effect of tumor and treatment-related variables on the rates of survival and local recurrence. Fifty-nine (95 per cent) of the patients had had an operation at another hospital before being referred to us. Twenty-nine (47 per cent) of the sixty-two tumors were high-grade, forty-two (68 per cent) were small (five centimeters or less), and thirty (48 per cent) were malignant fibrous histiocytomas. We followed a treatment strategy that consisted of repeat excision with the goal of obtaining wide margins. Excluding thirteen patients who had had a palpable local recurrence at the time of presentation, twenty (49 per cent) of forty-one patients who had had a marginal excision at another hospital had microscopic residual tumor on repeat excision. At a median of fifty-six months after the repeat excision, fifty (81 per cent) of the sixty-two patients had been continuously disease-free, one had no evidence of disease, eight had died of the disease, and three had died of other causes. The five-year rate of disease-free survival was 85 per cent (fifty-three of sixty-two patients). There were three local recurrences, all in patients who had had a marginal resection. No recurrences were noted in patients who had had a wide local excision of the tumor or of the previous operative field. Multivariate analysis revealed that a large tumor (greater than five centimeters), a marginal excision, and adjuvant radiation therapy were associated with a worse prognosis. Excellent rates of survival for patients who have a subcutaneous sarcoma, including those who have a large or high-grade tumor and those who have residual tumor following a previous operation, can be obtained with carefully planned operative treatment alone. We recommend operative excision or repeat excision with wide margins because of the high prevalence of residual tumor. Size is the most important tumor-related factor, and the operative margin is the most important treatment-related factor. The additional value of adjuvant radiation therapy remains unproved.     

Expression of functional MHC class II molecules by a mouse pro-B cell clone

OBJECTIVE: Pooled bronchoalveolar lavage fluid (BALF), the return of lavage, contains both bronchial and alveolar material which differ from each other. Artifacts may be created by filtering, centrifuging and washing cells before cytopreparation. This study presents reference values of healthy volunteers for the alveolar sample, ALF, cytopreparation being performed without filtration or centrifugation. METHODS: Eighteen healthy, non-smoking volunteers underwent a standard bronchoalveolar lavage using 10 aliquots of 20 ml of saline. Excluding the return of the first and second aliquots, the rest were pooled and examined cytologically, immunocytochemically and biochemically. The mean, standard deviation, and 95% confidence limits were calculated for the following variables: amount of return, estimated content of epithelial lining fluid (ELF), total and differential cell counts on filter and cytocentrifuge (CCF) preparations, computed cell counts per unit volume of ALF, distribution of lymphocyte subgroups CD3+CD2, CD4, CD8, CD19, CD25 and CD57, and the ratio of CD4 to CD8, the amounts of lymphocytes in the same subgroups per volume of ALF, and the concentrations of total protein, albumin, immunoglobulins A, G and M, hyaluronic acid, eosinophilic cationic protein (ECP), procollagen III aminoterminal propeptide (PCP) and beta 2-microglobulin in ALF and in ELF, as well as the ratios of the concentrations of the solutes in ALF to the same in serum. RESULTS: The 95% confidence limits of means for the most important variables were as follows: estimated ELF content 0.42-0.74%; total cells in ALF 76.6-143.0 x 10(6) l-1; distribution of inflammatory cells on filter and CCF slides: macrophages 74.9-83.6 and 81.4-90.1%, lymphocytes 13.1-22.5 and 8.1-16.4%, and neutrophils 1.0-4.1 and 0.7-2.7%, respectively; distribution of lymphocyte subsets: CD3+CD2 85.6-90.6%, CD4 44.3-53.1%, CD8 26.9-35.8%; concentration of solutes in ALF: total protein 44.8-61.3 mg l-1, albumin 15.4-22.2 mg l-1, IgA 1.8-3.4 mg l-1, IgG 3.1-6.1 mg l-1, IgM 0.05-0.26 mg l-1, hyaluronic acid 8.8-11.1 micrograms l-1, ECP 0.19-0.77 micrograms l-1, PCP 0.005-0.58 micrograms l-1, beta 2-microglobulin 62.2-81.5 micrograms l-1. CONCLUSIONS: Our results show that excluding the bronchial sample from ALF of volunteer subjects and omitting filtering and washing before cytopreparation produces cytologic, immunocytochemical and biochemical reference values with reasonable 95% confidence limits to be used in clinical settings.     

Screening demand-side management programs with a value-based test

A value-based test is presented for economic screening of electric utility demand-side management (DSM) programs. The widely used least cost test is valid if the programs do not alter the amount or value of energy services provided to customers. But, in general, DSM programs have such effects and, as a result, the value consumers receive is changed. A more general economic efficiency test, the most value test, provides a practical method for considering the effects of DSM on customer value. The version presented allows for multiple load periods and can account for rate impacts on several customer classes. Four typical DSM programs are evaluated as illustrations